Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex

Pacheco‐Quinto, Javier; Eckman, Christopher B.; Eckman, Elizabeth A.

doi:10.1016/j.neurobiolaging.2016.08.011

Cited by 33 publications

(25 citation statements)

References 62 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The differential cellular and subcellular localizations of NEP, NALIVAEVA AND TURNER 3451 BJP ECE-1, and ECE-2 suggest that they regulate distinct pools of Aβ with NEP able to degrade extracellular Aβ and ECE-1 and ECE-2 controlling intracellular pools in early endosomes and/or the endosomal/lysosomal compartments (Eckman et al, 2006;Pacheco-Quinto & Eckman, 2013). At the cellular level, ECE-1 is more broadly distributed in the brain than NEP or ECE-2 (Barnes, Walkden, Wilkinson, & Turner, 1997;Matsas, Kenny, & Turner, 1986;Pacheco-Quinto, Eckman, & Eckman, 2016), which are enriched in GABAergic neurons in the hippocampus and neocortex (Pacheco-Quinto et al, 2016). NEP2 shows a different subcellular localization from NEP (Whyteside & Turner, 2008) and does appear to have a significant contribution to Aβ metabolism in vivo, at least from transgenic studies in AD mouse models (Marr & Hafez, 2014).…”

Section: The Nep Familymentioning

confidence: 99%

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Nalivaeva

Turner

2019

British J Pharmacology

130

View full text Add to dashboard Cite

Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

show abstract

Section: The Nep Familymentioning

confidence: 99%

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Nalivaeva

Turner

2019

British J Pharmacology

130

View full text Add to dashboard Cite

show abstract

“…17 Previous work has shown that the enzymes responsible for degrading Aβ are expressed in interneurons. 18 The presence of endothelin-converting enzyme (ECE-2) and neprilysin in interneurons suggests the possibility that Aβ may have a role in the regulation of inhibition, acting as a neuropeptide important for interneuronal function. 18 Additionally, GABA receptors are altered in AD 19 with a varied pattern of GABA B receptor R1 protein (GBR1) expression throughout the hippocampus of AD patients.…”

Section: Introductionmentioning

confidence: 99%

“…18 The presence of endothelin-converting enzyme (ECE-2) and neprilysin in interneurons suggests the possibility that Aβ may have a role in the regulation of inhibition, acting as a neuropeptide important for interneuronal function. 18 Additionally, GABA receptors are altered in AD 19 with a varied pattern of GABA B receptor R1 protein (GBR1) expression throughout the hippocampus of AD patients. An increased GBR1 expression was identified in the CA4 and CA3/2 areas, yet was rapidly reduced in the CA1 region with advanced AD pathology and progression of neurofibrillary tangles (NFT) prior to neuronal cell death.…”

Section: Introductionmentioning

confidence: 99%

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

et al. 2020

View full text Add to dashboard Cite

Neuronal dysfunction and synaptic loss are major hallmarks of Alzheimer's disease (AD) which correlate with symptom severity. Impairment of the γ‐aminobutyric acid (GABA)ergic inhibitory interneurons, which form around 20% of the total neuronal network, may be an early event contributing to neuronal circuit dysfunction in neurodegenerative diseases. This study examined the expression of two of the main classes of inhibitory interneurons, parvalbumin (PV) and somatostatin (SST) interneurons in the temporal cortex and hippocampus of AD and control cases, using immunohistochemistry. We report a significant regional variation in the number of PV and SST interneurons with a higher number identified per mm2 in the temporal cortex compared to the hippocampus. Fewer SST interneurons, but not PV interneurons, were identified per mm2 in the temporal cortex of AD cases compared to control subjects. Our results support regional neuroanatomical effects on selective interneuron classes in AD, and suggest that impairment of the interneuronal circuit may contribute to neuronal dysfunction and cognitive decline in AD.

show abstract

“…ECE-2 localizes exclusively intracellularly, within membranes of E-L vesicles including autophagosomes, and in cultured cells, ECE-2 activity influences only intracellular Ab (17). We recently discovered that ECE-2 expression is largely restricted to somatostatincontaining interneurons in the cortex and hippocampus (58). If these neurons normally require substantial ECE-2 activity to maintain intracellular Ab homeostasis, it is conceivable that they are also especially vulnerable to insults that disrupt this activity.…”

Section: Discussionmentioning

confidence: 99%

Intracellular metalloprotease activity controls intraneuronal Aβ aggregation and limits secretion of Aβviaexosomes

et al. 2018

Self Cite

View full text Add to dashboard Cite

Accumulating evidence suggests that the abnormal aggregation of amyloid‐β (Aβ) peptide in Alzheimer's disease (AD) begins intraneuronally, within vesicles of the endosomal‐lysosomal pathway where Aβ is both generated and degraded. Metalloproteases, including endothelin‐converting enzyme (ECE)‐1 and ‐2, reside within these vesicles and normally limit the accumulation of intraneuronally produced Aβ. In this study, we determined whether disruption of Aβ catabolism could trigger Aβ aggregation within neurons and increase the amount of Aβ associated with exosomes, small extracellular vesicles derived from endosomal multivesicular bodies. Using cultured cell lines, primary neurons, and organotypic brain slices from an AD mouse model, we found that pharmacological inhibition of the ECE family of metalloproteases increased intracellular and extracellular Aβ levels and promoted the intracellular formation of Aβ oligomers, a process that did not require internalization of secreted Aβ. In vivo, the accumulation of intraneuronal Aβ aggregates was accompanied by increased levels of both extracellular and exosome‐associated Aβ, including oligomeric species. Neuronal exosomes were found to contain both ECE‐1 and ‐2 activities, suggesting that multivesicular bodies are intracellular sites of Aβ degradation by these enzymes. ECE dysfunction could lead to the accumulation of intraneuronal Aβ aggregates and their subsequent release into the extracellular space via exosomes.—Pacheco‐Quinto, J., Clausen, D., Pérez‐González, R., Peng, H., Meszaros, A., Eckman, C. B., Levy, E., Eckman, E. A. Intracellular metalloprotease activity controls intraneuronal Aβ aggregation and limits secretion of Aβ via exosomes. FASEB J. 33, 3758–3771 (2019). http://www.fasebj.org

show abstract

Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex

Cited by 33 publications

References 62 publications

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

Intracellular metalloprotease activity controls intraneuronal Aβ aggregation and limits secretion of Aβviaexosomes

Contact Info

Product

Resources

About